Optimisation of galenic forms plays an important role in the formulation of medicaments to achieve adequate pharmaceutical properties such as optimal drug release and convenience for the patient. For the preparation of a pharmaceutical composition capsules (Capsulae medicinales) are frequently used. The shell of the capsules often consists of biopolymers such as gelatine, starch or other suitable pharmaceutically inert matter like dried gels of macromolecular substances. The capsules are soluble, digestible or permeable under physiological conditions in vivo. Due to a number of advantageous properties capsules are frequently used to formulate solid, semisolid or liquid drugs: (a) even sensitive and technologically problematic pharmaceutical compositions can be formulated, (b) the drugs are protected from environmental hazards (light, air, humidity), (c) expiry date and shelf-life are increased, (d) high dosage reliability especially of liquid drugs, (e) optimal and ensured drug release characteristics (with or without sustained release effect), (f) convenient application with neutral taste and smell, (g) well tolerated, (h) unambiguous identification by shape, colour and imprint implying an increased drug safety. One problem with the use of orally applied capsules is the controlled release during the passage through stomach and intestine. Resistance to stomach acids to different degree can be achieved by coating with cellulose acetate phtalate, hydroxypropyl methyl cellulose phtalate or a varnish of acrylic resins.
Another galenic form for oral administration of drugs is the use of a matrix which is resistant to disintegration for the formulation of tablets. The matrix consists of e.g. cellulose ether or crosslinked amylose, as disclosed in U.S. Pat. No. 6,238,698 for tablets comprised of several layers including a matrix layer and an excipient layer which increases the resistance of the matrix layer to disintegration. U.S. Pat. No. 5,407,686 discloses a composition for the construction of a tablet consisting of multiple layers, one of which is a film coating comprising a soluble polymer and a plasticizer. Further galenic forms like microgranules, micelles or vesicles have been disclosed, some of them reporting increased resistance to degradation or sustained release.
The use of the surface active proteins of the present invention as novel excipients may contribute significantly to the improvement of these galenic forms in the preparation of e.g. matrix tablets, aerosols, suspensions or liquid medicines.
U.S. Pat. No. 5,538,738 describes a system providing sustained release of medicinal or biological material by admixture of hydroxycarboxylic acids to a dosage form to modify retard systems or depot materials. WO 99/042086 proposes a prolonged release galenic form comprising an absorption-promoting agent based on lipid substances. U.S. Pat. No. 4,859,469 discloses novel galenic forms comprising microgranules being coated with a microporous membrane consisting of a synthetic polymer and a pharmacologically acceptable adjuvant.
None of the above patents describes the use of surface active proteins like for example hydrophobins, chaplins, curlins or latherin, as surface active excipients in the preparation of pharmaceutical forms. The present invention therefore provides a means of endowing polymers with advantageous acid-resistant and prolonged-release characteristics properties, i.e. for a variety of galenic uses as outlined above. Envisioned is the admixture of surface active proteins within the process of preparation of polymers or the coating of polymers for pharmaceutical use. The most prominent advantage is that the passage of drugs in the galenic form according to the present invention through the stomach is allowed, when drug release mainly in the intestine is indicated or even a controlled release in the intestine is desired.
Surface active agents can change the chemical and physical properties of the interface when such agents are adsorbed onto the surfaces of dispersed particles. Amphiphilic surface active agents consist of hydrophobic and hydrophilic segments. The hydrophobic part will adsorb on a non-polar surface or be attracted by a non-polar phase whereas the hydrophilic segment will be attracted to a polar surface or phase. Such surface active agents can thus be used to make hydrophilic surfaces hydrophobic and hydrophobic surfaces hydrophilic. Certain surface active agents can self-assemble at any hydrophilic-hydrophobic interface into an amphipathic film. Such self-assembly can significantly improve the properties of a (bio)polymer. At liquid/water interfaces, surface active agents reduce the water surface tension which results in a change of the contact angle of a water-droplet. This parameter can be used for the measurement of the activity of a surface active agent. The use of surface active agents can contribute significantly to the improvement of galenic forms in the preparation and performance of e.g. capsules, pills, tablets, microgranules and suppositories.
Some proteins of natural origin act as surface active agents. Surface active proteins comprise, but are not limited to, hydrophobins, chaplins, curlins or latherin.
Hydrophobins are small cystein-rich fungal surface active proteins of about 10 kDa in size, which self-assemble at hydrophilic-hydrophobic surfaces or interfaces into highly insoluble amphipathic layers. They are characteristic of filamentous fungi, for example of Schizophyllum commune or Trichoderma reesei and are found as structural proteins on surfaces of aerial structures of fungi where the hydrophobic coating is proposed to have a protecting role both against desiccation, wetting and protecting the conidia of filamentous fungi against extreme environmental conditions. Two classes of hydrophobins have been distinguished based on aqueous solubility and hydropathy. Hydrophobins can be isolated from natural sources, but it is also possible for hydrophobins that do not occur naturally to be synthesised by means of chemical and/or biotechnological methods of preparation. The use of engineered SC3 to achieve surface modifications, namely wettability and enhanced growth of fibroblasts, has been described by Scholtmeijer, K. et al. (Surface modifications created by using engineered hydrophobins, Appl. Environ. Microbiol. 2002, 68(3): 1367-73).
EP1254158 describes a general method for coating a surface with hydrophobin. WO96/41882 proposes the use of hydrophobins as emulsifiers, thickeners or surface-active substances, for rendering hydrophobic surfaces hydrophilic, for improving the water resistance of hydrophilic substrates, and for preparing oil-in-water emulsions or water-in-oil emulsions.
Also proposed are pharmaceutical uses, such as the preparation of ointments or creams, and cosmetic uses, such as skin protection or the preparation of hair shampoos or hair conditioners (US2003/217419). Cosmetic uses are also proposed in WO 06/136607 where the binding properties of hydrophobins to keratin or to mucosa or teeth are utilized to direct cosmetic effector molecules, e.g. in the form of compositions or conjugates with a hydrophobin, to the desired site of action (hair, nails, skin). A method of binding a compound of interest (e.g. enzyme, antibody, nucleic acid) to a surface using a hydrophobin-like coating is described in WO04/00880.
However, the use of hydrophobins according to prior art is mostly related to the modification of surface properties by coating with a hydrophobin-containing solution. Apart from implementations as emulsifiers and thickeners stated above the use of hydrophobins or other surface active proteins as excipients in galenics has not been described to date.